Once daily pharmaceutical tablet having a unitary core

ABSTRACT

A controlled release tablet is disclosed which comprises: 
     (a) a homogeneous compressed core which comprises: 
     (i) a medicament which is very slightly soluble to practically insoluble in water at 25° C.; 
     (ii) a water soluble osmotic compound 
     (iii) one or more osmotic polymers; and 
     (b) a membrane coating which completely covers said core tablet which comprises a mixture of a: 
     (i) a water insoluble pharmaceutically acceptable polymer; and 
     (ii) a pH dependent polymer such as an enteric coating polymer, the weight ratio of the pH dependent polymer to the water insoluble pharmaceutically acceptable polymer being 0.1:1 to 0.75:1. 
     A controlled release tablet which comprises: 
     (a) a medicament 
     (a) a homogeneous compressed core which comprises: 
     (i) a medicament; 
     (ii) a water soluble osmotic compound 
     (iii) one or more osmotic polymers; and 
     (b) a membrane coating which completely covers said core tablet which comprises a mixture of: 
     (i) a water insoluble pharmaceutically acceptable polymer; and 
     (ii) an enteric polymer.

BACKGROUND OF THE INVENTION

The present invention relates to controlled release unit doseformulations of pharmaceuticals. In the prior art, many techniques havebeen used to provide controlled and extended-release pharmaceuticaldosage forms in order to maintain therapeutic serum levels ofmedicaments and to minimize the effects of missed doses of drugs causedby a lack of patient compliance.

In the prior art, extended release tablets containing osmotic tabletshave been described and manufactured which have had an osmoticallyactive drug core surrounded by a semipermeable membrane. The core isdivided into two layers (compositions) one of which contains the activedrug and the other contains a push layer of pharmacologically inactiveingredients which are osmotically active in the presence ofgastrointestinal fluids. An outer water impermeable coating covers thetablet which is provided with an aperture that is formed by laserdrilling an orifice to allow the drug to be pushed out of the tablet. Aproduct of this type is disclosed in U.S. Pat. Nos. 4,783,337;4,765,989; 4,612,008; and 4,327,725 and is sold commercially asProcardia XL®. Other controlled release compositions include thosedescribed in U.S. Pat. Nos. 3,948,254 and 4,036,227.

The osmotic dosage forms that are disclosed in U.S. Pat. No. 4,783,337are described as having a passageway which includes an aperture,orifice, hole, porous element, hollow fiber, capillary tube, microporousinsert, pore, microporous overlay or bore which extends through thesemipermeable lamina wall into a drug layer. The patent also states thatthe passageway may be formed by mechanical drilling, laser drilling,eroding and erodible element, extracting, dissolving, bursting orleaching a passageway-former from the wall of the osmotic dosage form(col. 14, line 35 et seq.) which are pre-formed in the tablet during themanufacturing process. The only exemplified technique of forming apassageway in U.S. Pat. No. 4,783,337 is the use of a laser to drill ahole in the outer layer of the tablet and the dosage forms are all basedon a drug layer superimposed on a secondary layer.

U.S. Pat. No. 4,285,987 described an osmotic tablet which had a laserdrilled aperture into the core of the tablet. The laser drilled hole wasplugged with leachable sorbitol which was leached out in the presence ofgastrointestinal fluid.

U.S. Pat. No. 4,503,030 discloses an osmotic device for delivering drugsto the stomach and the intestine. This device has a shaped wall placedaround a compartment which is described as a compartment which maintainsits physical and chemical integrity in the stomach but loses itschemical and physical integrity in the intestine. U.S. Pat. No.4,587,117 describes an oral osmotic device which has a shaped wall whichloses its integrity at a pH of 3.5 to 8.0, a compartment and apassageway from the compartment to the exterior of the medical device.

The present invention is concerned with providing an osmotic tablet forhighly water insoluble medicaments that avoids the need to have aseparate “push” layer in the core which contains no medicament and whichavoids the need to have a pre-formed passageway in the tablet to allowthe drug to be pushed out of the core.

SUMMARY OF THE INVENTION

The present invention is directed to a controlled release dosage formwhich comprises:

(a) a homogeneous compressed core which comprises:

(i) a medicament which is very slightly soluble to practically insolublein water at 25° C.;

(ii) a water soluble osmotic compound

(iii) one or more osmotic polymers; and

(b) a membrane coating which completely covers said core tablet whichcomprises a mixture of a:

(i) a water insoluble pharmaceutically acceptable polymer; and

(ii) a pH dependent polymer such as an enteric coating polymer, theweight ratio of the pH dependent polymer to the water insolublepharmaceutically acceptable polymer being 0.1:1 to 0.75:1.

It is a primary object of the invention to provide a controlled releasepharmaceutical tablet which has an osmotic core covered with an externalpolymer membrane that provides therapeutic blood levels of a medicamentwith once a day administration.

It is also an object of the invention to provide an osmotic tablet whichhas a homogeneous core composition.

It is also an object of the present invention to provide a controlledrelease pharmaceutical tablet that has a homogeneous osmotic core and nopre-formed aperture in the external polymeric membrane.

It is also an object of this invention to provide a controlled releasepharmaceutical tablet having only a homogeneous osmotic core wherein theosmotic core component may be made using ordinary tablet compressiontechniques.

These and other objects of the invention will become apparent from theappended specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which compares the mean plasma concentration ofProcardia XL® (a) and a nifedipine tablet (b) prepared according toExample 1 of the present invention in a crossover study involving 6fasting human volunteers.

FIG. 2 is a cross-section of a tablet of the invention which shows theextrusion of a portion or portions of the core through a portion of theedge of the tablet which is observed within one hour after a tablet isplaced in an aqueous fluid.

DETAILED DESCRIPTION OF THE INVENTION

Various medicaments may be administered using the osmotic tablet of thepresent invention. These medicaments include medicaments which are veryslightly soluble to practically insoluble in water at 25° C. The termvery slightly soluble is used to include those medicaments which aresoluble at a level of one part of solute to 1,000 parts of water and theterm practically insoluble is used to include those substances which aresoluble at a level of 1 part of solute to more than 10,000 parts ofwater.

Examples of categories of these medicaments include anti-hypertensives,calcium channel blockers, analgesics, anti-neoplastic agents,anti-microbials, anti-malarials, non-steroidal anti-inflammatory agents,diuretics, anti-arrythmia agents, hypoglycemic agents and the like.Specific examples of medicaments include nifedipine, nisoldipine,nicardipine, nilvadipine, felodipine, bendroflumethazide, acetazolamide,methazolamide, chlorpropamide, methotrexate, allopurinol, erythromycin,hydrocortisone, triamcinolone, prednisone, prednisolone, norgestrel,norethindone, progesterone, norgesterone, ibuprofen, atenolol, timolol,cimetidine, clonidine, diclofenac, glipizide, lovastatin, fluvastatin,simvastatin, pravastatin, fexofenadine, and the like. Useful watersoluble medicaments include various therapeutic agents such asdecongestants, antihistamines, analgesics, sedatives, anti-inflammatory,anti-depressants, antihypertensives and the like at therapeutic dosagelevels.

Examples of specific medicaments which may be utilized, at therapeuticdose levels, in the controlled release tablets of the invention includeephedrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine,diphenhydramine, dimenhydramine, indomethacin, labetalol, albuterol,haloperidol, amitriptyline, clofenac, clonidine, terfenadine, fentanyl,and the like which are in the form of a water soluble salt such as thehydrochloride or sodium salt or in the from of an ester, ether, amide,complex or the like.

The unitary core osmotic tablet formulation of the invention whichcontains nifedipine as the medicament has been demonstrated to havebioequivalent pharmacokinetic performance (i.e., maintain a sustained 24hour drug plasma levels) when compared with multiple layer-preformedaperture tablets which require a complex segmented osmotic core.

In the case of nifedipine, the core of the controlled release tablet ofthe present invention is preferably made from an amorphous nifedipinewhich may be formed from crystalline nifedipine which is dissolved in asolvent such as acetone and formed into granules by spraying thesolution on an excipient which comprises a water solublepharmaceutically acceptable polymer binder and a water soluble osmoticagent. In the alternative, crystalline nifedipine may be used.

The medicament, the pharmaceutically acceptable water soluble polymerbinder and the water soluble osmotic agent are first formed into agranulation which is subsequently blended with a water swellable osmoticpolymer and suitable excipients to form a composition which may becompressed into tablets. In the alternative, the water solublepharmaceutically acceptable polymer may be combined with the medicamentand the water soluble osmotic compound and the water swellable osmoticpolymer. After a granulation is formed from this blend, the granules maybe tabletted with or without the addition of an additional quantity of awater soluble compound and/or the water swellable osmotic polymer. Atabletting machine is used to compress the granulation mixture into acore tablet having a homogeneous core. The homogeneous core issubsequently completely coated with a modified polymeric membrane toform the controlled release tablet of the invention.

It is believed that as water passes through the membrane on the surfaceof the tablet of the invention, the core swells and increases thepressure inside the tablet. This causes a very slight expansion of thepartially hydrated core which is controlled by the use of a relativelysmall amount of the water swellable polymer.

The expansion of the core will cause the membrane to open to relieve theinternal pressure. Once the initial opening or openings are formed, theswelling effect of the core components will cause the contents of thecore to extrude through the initial opening without completedisintegration of the membrane. The internal pressure which is exertedon the membrane by the swelling and expanding osmotic core is relievedby the passage of the first portions of the core contents through theinitial openings. This effect is unexpected because it could not havebeen predicted that small, randomly formed openings in the membranewould form and relieve the internal pressure by gradually controlledrelease than dose dumping the entire core contents by a bursting ordisintegration of the membrane. It is believed that the formation of thesmall openings, without initial loss of the integrity of the rest of themembrane by uncontrolled expansion of the osmotic core, is responsiblefor the 24 hour therapeutic blood level which is achieved by thecontrolled release tablet of the invention.

FIG. 2 shows a cross-section of a tablet of the invention whichillustrates the internal structure of the tablet with core element 10and membrane 12. The inherent effect of the surface tension results in arelatively thin membrane at edges 14 and 16 is shown by thecross-section. The relatively thin membrane at edges 14 and 16 istypical of the membrane thicknesses obtained when a controlled releasecoating is applied to any tablet core. The extruding portions of thecore 18 which is observed after the tablet is placed in an aqueous fluidappear to resemble an irregularly shaped elastic mass of a portion ofthe core tablet.

The controlled release tablet of the invention has been used toadminister the calcium channel blocker nifedipine.

The preferred water soluble osmotic agents include water soluble organicand inorganic compounds such as sucrose, lactose, dextrose, sodiumchloride, sorbic acid, potassium chloride, polyethylene glycol (weightav. molecular weight 380-420), propylene glycol and mixtures thereof.These materials are utilized at a level of 20-60% and preferably from35-50% based on the weight of the core of the tablet.

The core composition will contain one or more osmotic polymers. If twoosmotic polymers are used, one osmotic polymer may be a pharmaceuticallyacceptable, water soluble polyvinyl pyrrolidone having a weight averagemolecular weight of 25,000 to 200,000. Other pharmaceutically acceptablewater soluble polymers include hydroxy propyl cellulose,hydroxyethylcellulose and the like.

The pharmaceutically acceptable, water soluble osmotic polymer may beemployed in an effective amount that will exert an osmotic effect on therelease of the calcium channel blocking agent. These amounts willgenerally be from about 15 to 40%, preferably from about 20 to 30% basedon the weight of the compressed tablet core.

The composition of the core also preferably includes as a second osmoticpolymer, a pharmaceutically acceptable, water swellable osmotic polymersuch as polyethylene oxide having a weight average molecular weight of100,000 to 6,000,000. Other water swellable osmotic polymers includehydroxypropyl methylcellulose, poly(hydroxy alkyl methacrylate) having amolecular weight of from 30,000 to 5,000,000; poly(vinyl)alcohol, havinga low acetal residue, which is cross-linked with glyoxal, formaldehydeor glutaraldehyde and having a degree of polymerization of from 200 to30,000; a mixture of methyl cellulose, cross-linked agar andcarboxymethyl cellulose; a water insoluble, water swellable copolymerproduced by forming a dispersion of a finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, butylene or isobutylenecross-linked with from 0.001 to 0.5 moles of saturated cross-linkingagent of saturated cross-linking agent per mole of maleic anyhydride inthe copolymer; Carbopol® acidic carboxy polymers having a molecularweight of 450,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linkedwater swellable indenemaleic anhydride polymers; Goodrite® polyacrylicacid having a molecular weight of 80,000 to 200,000; starch graftcopolymers; Aqua-Keeps® acrylate polymer polysaccharides composed ofcondensed glucose units such as diester cross-linked polyglucan and thelike. Other polymers which form hydrogels are described in U.S. Pat.Nos. 3,865,108; 4,002,173 and 4,207,893 all of which are incorporated byreference. The pharmaceutically acceptable, water swellable polymers maybe employed in an effective amount that will control the swelling of thetablet core. These amounts will generally be from about 5 to 15%,preferably from about 7 to 12% based on the weight of the compressedtablet core.

The membrane coating which completely covers said core comprises a waterinsoluble pharmaceutically acceptable polymer in combination with anenteric polymer. Suitable water insoluble polymers include celluloseesters, cellulose ethers and cellulose ester ethers. These materialsinclude cellulose acylate, cellulose ethyl ether, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-,di- and tricellulose alkyls, mono-, di- andtricellulose aroyls and the like. Cellulose acetate is the preferredpolymer. Other water insoluble polymers are disclosed in U.S. Pat. No.4,765,989 which is incorporated by reference. If desired the abovepolymer may be combined with from 10 to 40%, and preferably 20-30% of apH sensitive polymer which functions as an enteric polymer in that itdoes not begin to disperse until pH conditions in excess of the stomachregion are encountered. Stated differently, a weight ratio of 0.1:1 to0.75:1 or preferably 0.11:1 to 0.66:1 or more preferably 0.25:1 to0.42:1 of enteric polymer to water insoluble polymer may be used.Generally, the pH sensitive material or enteric polymers do not degradeand begin to release the active drug until a pH above 3.0 is reached andpreferably above 5.5. Materials such as Eudragit L (poly(methacrylicacid methylmethacrylate); 1:1 ratio; MW No. Av. 135,000—USP Type A) orEudragit S (poly(methacrylic acid, methylmethacrylate); 1:2 ratio; MWNo. Av. 135,000—USP Type B). hydroxypropyl methyl cellulose phthalate,cellulose acetate phthalate, polyvinyl acetate phthalate and the likemay be used as the pH sensitive or enteric polymer to modify thepermeability of the membrane coating around the core.

Generally, the membrane coating around the core will comprise from about1 to 4% and preferably about 2% based on the total weight of the coretablet.

The water insoluble polymer-enteric polymer mixture may contain anoptional plasticizer or a water soluble channeling agent as themodifier. The water soluble channeling agent is a material thatdissolves in water to form a porous polymer shell that allows water tobe imbibed into the core. This material is used in a sufficient amountto control the lag time for the formation of the initial openings of thecoated tablet. These materials include water soluble organic andinorganic compounds such as sucrose, lactose, dextrose, sodium chloride,sorbic acid, potassium chloride, polyethylene glycol (weight av.molecular weight 380-420), propylene glycol and mixtures thereof. Theamount of channeling agent may be from 0-50% and preferably from 10-30%based on the total dry weight of the coating composition.

The water insoluble polymer-enteric polymer mixture may be plasticizedwith a plasticizing amount of a plasticizer. The preferred plasticizeris triacetin but materials such as acetylated monoglyceride, rape seedoil, olive oil, sesame oil, acetyltributylcitrate,acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate,diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate,dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate,and the like. Depending on the particular plasticizer or water solublechanneling agent, amounts of from 1% to 40%, and preferably 10 to 30% ofthe modifier based on the total weight of the water insoluble polymer,water soluble polymer and the modifier may be utilized.

In the preparation of the tablets of the invention, various conventionalwell known solvents may be used to prepare the granules and apply theexternal coating to the tablets of the invention. In addition, variousdiluents, excipients, lubricants, dyes, pigments, dispersants etc. whichare disclosed in Remington's Pharmaceutical Sciences, 1995 Edition maybe used to optimize the formulations of the invention. In thealternative, dry granulation techniques may used to prepare formulationfor making compressed tablets.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1

Tablets having the following formula are prepared as follows:

I Amorphous Granulation nifedipine (crystalline) 16.5% povidone¹, USP49.5% lactose (anhydrous) 31.0% sodium lauryl sulfate  3.0% acetone*(Five times the amount of nifedipine) isopropyl alcohol* (Five times theamount of nifedipine) ¹weight average molecular weight = 50,000; dynamicviscosity (10% w/v solution at 20° C.) = 5.5-8.5 m Pa s. *acetone andisopropyl alcohol are evaporated during the granulation process.

(a) The crystalline nifedipine is first dispersed in acetone and thenthe povidone is added with stirring until a uniform mixture is formed.The isopropyl alcohol is then added and mixed until a clear solution isformed. The sodium lauryl sulfate is added and the product iscontinuously stirred until it is used.

(b) The lactose is placed in a fluidized bed dryer to make granules. Thesolution of the nifedipine, which has been separately prepared in step(a), is sprayed onto the lactose and a granulation containing amorphousnifedipine is obtained. After completion of the granulation step, thedrying cycle is initiated. The drying is continued until the moistureloss on drying (LOD) is not more than 2.5%.

II Tabletting Amorphous granules from (I) 60.6% lactose(anhydrous) 24.4%poly(ethyleneoxide)², NF 10.0% glyceryl monostearate³  5.0% ²Polyox ®WSR Coagulant; approximate molecular weight = 5,000,000 ³Myvaplex 600

(c) A tablet core is made by blending 10.0% of poly (ethyleneoxide), NF;5.0 wt % of glyceryl monostearate 24.4% lactose; and 60.6% of thegranules from step (b), based on the total weight of all ingredients.Core tablets weighing 330 mg each are made in a tablet press machinewith 0.3410″ standard concave punches and die.

III Color Coating Opadry Yellow⁴ 75% sodium chloride 25% waterqs(evaporated during processing) ⁴polyethylene glycol 4000; polysorbate80; FD&C yellow No.10 aluminum lake; and FD&C red #40 aluminum lake

(d) The yellow color suspension is applied to the tablets prepared inStep (c) in a perforated coating pan. The coating level is 4% by weight.

The color coating is to protect the drug from light.

IV Sustained Release Coating cellulose acetate (398-3)⁵ 60% EudragitS100 20% triacetin 5% PEG 400 5% sucrose, micronized 10% acetone qs(evaporated during processing) ⁵acetyl content 39.8%)

(e) A sustained release coating is applied to the tablet prepared inStep (d) by coating the tablets in a fluidized-bed coater. The coatinglevel is 2% for this membrane.

A cross-section of a dissolving tablet of Example 1 is shown in FIG. 2.The core 10 is surrounded with membrane 12. At the side (14, 16) of thetablet, the membrane which is formed by coating a liquid onto thecompressed tablet core, tends to be thinner than on the larger convexsurfaces of the tablet. The opening of the tablet and extruded contents18 are illustrations of the phenomenon which takes place when the coatedtablets of the invention are placed in an aqueous fluid.

EXAMPLE 2

Tablets having the following formula are prepared as follows:

I Amorphous Granulation nifedipine (crystalline) 10.5% povidone¹, USP31.6% lactose (anhydrous) 45.5% sodium lauryl sulfate  1.9%poly(ethyleneoxide)², NF 10.5% acetone* (Five times the amount ofnifedipine) isopropyl alcohol* (Five times the amount of nifedipine)¹weight average molecular weight = 50,000; dynamic viscosity (10% w/vsolution at 20° C.) = 5.5-8.5 m Pa s. ²Polyox ® WSR Coagulant;approximate molecular weight = 5,000,000 *acetone and isopropyl alcoholare evaporated during the granulation process.

(a) The crystalline nifedipine is first dispersed in acetone and thenthe povidone is added with stirring until a uniform mixture is formed.The isopropyl alcohol is then added and mixed until a clear solution isformed. The sodium lauryl sulfate is added and the product iscontinuously stirred until it is used.

(b) The lactose, the polyoxyethylene and the glyceryl monostearate areplaced in a fluidized bed dryer to make granules. The solution of thenifedipine, which has been separately prepared in step (a), is sprayedonto the lactose and a granulation containing amorphous nifedipine isobtained. After completion of the granulation step, the drying cycle isinitiated. The drying is continued until the moisture loss on drying(LOD) is not more than 2.5%.

II Tableting Amorphous granules from (I) 95.0% glyceryl monostearate³ 5.0% ³Myvaplex 600

Core tablets weighing 330 mg each are made in a tablet press machinewith 0.3410″ standard concave punches and die.

III Color Coating Opadry Yellow⁴ 75% sodium chloride 25% waterqs(evaporated during processing) ⁴hydroxypropylmethyl cellulose,titanium dioxide, polyethylene glycol 4000; polysorbate 80; FD&C yellowNo.10 aluminum lake; and FD&C red #40 aluminum lake

(d) The yellow color suspension is applied to the tablets prepared inStep (c) in a perforated coating pan. The coating level is 4% by weight.

The color coating is to protect the drug from light.

IV Sustained Release Coating cellulose acetate (398-3)⁵ 60% EudragitS100 20% triacetin 5% PEG 400 5% sucrose, micronized 10% acetone qs(evaporated during processing) ⁵acetyl content 39.8%)

(e) A sustained release coating is applied to the tablet prepared inStep (d) by coating the tablets in a fluidized-bed coater. The coatinglevel is 2% for this membrane.

A cross-section of a dissolving tablet of Example 1 is shown in FIG. 2.The core 10 is surrounded with membrane 12.

If desired, the membrane coated tablet may be overcoated with an entericcoating such as the following:

hydroxy propyl methyl cellulose phthalate 70% (releases at pH 5.5) poreforming agent 0-30% or 5-25% talc, U.S.P. (no pore former) 23%acetyltributyl citrate (no pore former)  7% acetone (evaporated duringprocessing)

The overcoat is coated onto the membrane coated tablets to add 2 to 5 wt% and preferably about 4.3% The term “%” as used herein refers to weightpercent.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

We claim:
 1. A controlled release tablet which comprises: (a) ahomogeneous compressed core which comprises: (i) a medicament which isvery slightly soluble to practically insoluble in water at 25° C.; (ii)a water soluble osmotic compound (iii) one or more osmotic polymerswhich comprise poly(ethylene oxide); and (b) a membrane coating whichcompletely covers said core tablet which comprises a mixture of a: (i) awater insoluble pharmaceutically acceptable polymer; and (ii) a pHdependent polymer such as an enteric coating polymer, the weight ratioof the pH dependent polymer to the water insoluble pharmaceuticallyacceptable polymer being 0.1:1 to 0.75:1.
 2. A controlled releasepharmaceutical tablet as defined in claim 1 wherein the medicament is acalcium channel blocker compound.
 3. A controlled release pharmaceuticaltablet as defined in claim 2 wherein the medicament is nifedipine.
 4. Acontrolled release pharmaceutical tablet as defined in claim 1 whichincludes two osmotic polymers.
 5. A controlled release pharmaceuticaltablet as defined in claim 1 wherein one of the osmotic polymers is awater swellable osmotic polymer.
 6. A controlled release pharmaceuticaltablet as defined in claim 5 wherein the membrane around the corecontains an enteric polymer which is a methacrylic acid/methylmethacrylate polymer.
 7. A controlled release pharmaceutical tablet asdefined in claim 1 wherein the water insoluble polymer in the membranearound the core is a water insoluble cellulose derivative.
 8. Acontrolled release pharmaceutical tablet as defined in claim 7 whereinthe water insoluble cellulose derivative in the membrane around the coreis cellulose acetate.
 9. A controlled release pharmaceutical tablet asdefined in claim 1 wherein the mixture of the water insoluble polymerand the enteric polymer contain a plasticizer.
 10. A controlled releasepharmaceutical tablet as defined in claim 1 wherein the plasticizer istriacetin.
 11. A controlled release pharmaceutical tablet as defined inclaim 9 wherein the mixture of the water insoluble polymer and theenteric polymer contain a water soluble channeling agent.
 12. Acontrolled release pharmaceutical tablet as defined in claim 9 whereinthe mixture of the water insoluble polymer and the enteric polymer isovercoated with an additional layer of an enteric polymer.
 13. Acontrolled release pharmaceutical tablet as defined in claim 12 whereinthe enteric polymer overcoat is hydroxypropyl methylcellulose phthalatewhich is plasticized with acetyltributyl citrate.
 14. A controlledrelease tablet which comprises: (a) a homogeneous compressed core whichcomprises: (i) a medicament which is very slightly soluble topractically insoluble in water at 25° C.; (ii) a water soluble osmoticcompound (iii) poly(ethylene oxide); and (b) a membrane coating whichcompletely covers said core tablet which consists essentially of amixture of a: (i) cellulose acetate; (ii) a plasticizer; (iii) a watersoluble channeling agent; and (iv) poly(methacrylicacid-methylmethacrylate polymer having a 1:2 ratio of polymethacrylicacid to methylmethacrylate and a number average molecular weight of135,000, the weight ratio of cellulose acetate to said poly(methacrylicacid, methylmethacrylate polymer being 0.1:1 to 0.75:1.